Perspective Stem cell transplantation for treatment of severe autoimmune diseases: current status and future perspectives

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1 (2000) 25, Macmillan Publishers Ltd All rights reserved /00 $ Perspective Stem cell transplantation for treatment of severe autoimmune diseases: current status and future perspectives Department of Medicine, Kuopio University Hospital, Kuopio, Finland Summary: Autoimmune diseases include a heterogenous group of disorders with variable presentation and severity. Immunosuppressive and immunomodulatory therapies are often used for treatment with considerable success in some cases. These diseases may also be severe and refractory to conventional treatment. Thus more aggressive intervention might be indicated in a subset of patients. Animal studies suggest that high-dose therapy supported by stem cell transplantation may lead to remissions in experimental autoimmune disease models. Anecdotal case reports suggest that the same may be the case in some human autoimmune diseases as well. This review attempts to summarise some current concepts and future perspectives on stem cell transplantation in the treatment of severe autoimmune diseases. (2000) 25, Keywords: stem cell transplantation; autoimmune diseases Autoimmune diseases (ADs) include a heterogenous group of disorders with either organ-specific or systemic manifestations. The pathogenesis of these diseases is poorly understood. Since the etiology is unknown, cause-related treatment is not possible. Current therapeutic approaches are based on agents that suppress or modify the immune system. Although many ADs are not life-threatening as such, some of them can cause functional disability and progress despite various therapeutic attempts. The diseases may impose important restraints on the patients daily activities and have important socioeconomic consequences. Some ADs are severe and life-threatening either in the short-term (eg systemic vasculitides) or the long-term (eg progressive systemic sclerosis, rheumatoid arthritis with secondary amyloidosis). Conventional treatment of ADs may be costly and associated with important side-effects. Aggressive interventions including high-dose therapy supported by Correspondence: Dr E Jantunen, Department of Medicine, Kuopio University Hospital, POB 1777, Kuopio, Finland Received 8 July 1999; accepted 14 October 1999 stem cell transplantation (SCT) might therefore be indicated in a subset of patients with poor prognostic features. Allogeneic SCT has traditionally been reserved for treatment of malignant or non-malignant but severe diseases (congenital immunodeficiency syndromes, aplastic anaemia, thalassaemia). The curative potential of this approach has been clearly demonstrated in several diseases including some of putative autoimmune origin (eg aplastic anaemia), but important treatment-related mortality has to date hindered the use of allogeneic SCT in the treatment of less severe conditions. Autologous stem cell transplantation (ASCT) has become an established form of therapy for some malignant diseases. Recent advances in stem cell technology and supportive care have considerably decreased the toxicity of this approach. Recently, ASCT has been also considered as an experimental therapy in severe and refractory autoimmune diseases. 1 7 Rationale for stem cell transplantation in the treatment of autoimmune diseases The purpose of SCT in the treatment of ADs is to allow delivery of intensive chemotherapy or chemoradiotherapy in order to cause severe immunosuppression or even total immunoablation. Infused stem cells then repopulate the patient and give rise to new haematopoiesis and a complete immune system. In allogeneic SCT, the immune system is provided by the donor cells. In ASCT, autologous progenitor cells give rise to differentiated cells, including those involved in various immune functions. Experimental background Several animal models of autoimmunity have been developed. These models have facilitated study of the efficacy of high-dose therapy supported by SCT in the treatment of these disorders. Although more detailed discussion of this topic is beyond the scope of this review, some general aspects will be briefly summarised. Important disease models with regard to human ADs include experimental autoimmune encephalomyelitis, 8,9 adjuvant-induced arthritis 10 and spontaneous lupus erythematosus. 11,12 Allogeneic, syngeneic and autologous SCT

2 352 have been tried in the treatment of these disease models. 13,14 TBI-based regimens have been applied in most studies. It is difficult to extrapolate directly from these disease models to human ADs. However, these studies suggest that myeloablative therapy supported by SCT may result in remission or induction of immune tolerance in a variety of animal models of autoimmunity. Systemic lupus erythematosus (SLE) Patients with severe forms of SLE including those with vasculitis of central nervous system might be considered for ASCT. Also, patients with important renal involvement may benefit from this approach. No published series on ASCT in SLE are at present available, but some promising case reports have been published. 34,35 Clinical experiences so far Several anecdotal case reports suggest that allogeneic SCT performed for another indication have led to objective responses or even cures in patients with AD including rheumatoid arthritis, 15,16 multiple sclerosis, 17 psoriasis 18 and ulcerative colitis. 18 Experience is less impressive in patients who have received ASCT for treatment of malignant disease and who have had a concomitant AD. Remissions or responses have been reported in patients with Crohn s disease, 19 ulcerative colitis, 20 rheumatoid arthritis, 21 nonerosive polyarthritis, 22 psoriasis 21 and systemic lupus erythematosus. 23,24 On the other hand, early relapses of ADs after ASCT have also been reported. 25,26 During the last few years more than 100 ASCTs for ADs have been reported to the EULAR/EBMT database. 27 Experience is still very preliminary and it will take several years before any firm conclusions can be drawn on the possible role of ASCT in the treatment of severe forms of diseases with putative autoimmune etiology. Rheumatic diseases Systemic sclerosis (SSc) Pilot studies are ongoing in the treatment of SSc with ASCT. Early experience suggests stabilization or improvement in some patients Due to generally poor prognosis of a subset of patients with SSc and lack of effective therapeutic options, this disease is at present the most frequent rheumatological indication for ASCT. Experience in this disease may accumulate quite soon to form a basis for further trials. Other rheumatic diseases Patients with systemic vasculitis are often treated with intravenous CY. If these patients fail to respond to conventional therapy or progress on therapy, more intensive therapy including high-dose CY with or without ASCT might be considered. Juvenile arthritis may be resistant to conventional therapy. A pilot study in this disease is ongoing in the Netherlands and the preliminary results hold some promise. 36 Multiple sclerosis Multiple sclerosis (MS) has been to date the most common single indication for ASCT in the area of ADs. A recent pilot study performed in Greece 37 described early experiences in 15 patients with progressive MS transplanted with unselected peripheral blood progenitor cells after conditioning with BEAM plus antithymocyte globulin. With a median follow-up of 6 months, some patients showed a functional improvement, but there were some early relapses. Burt and co-workers 34,38 have used high-dose CY plus TBI followed by infusion of T cell-depleted progenitor cells: all three transplanted patients showed objective improvement. 39 Based on these preliminary experiences, a phase II trial on ASCT in patients with MS is now ongoing in several European centres, and if the early experiences on feasibility and efficacy of ASCT are confirmed, a randomised trial should follow. Beta-interferon can modulate to a certain extent the clinical course of MS and perhaps should be compared with ASCT in future trials. Rheumatoid arthritis (RA) Snowden and co-workers 31 used cyclophosphamide (CY) 100 mg/kg or 200 mg/kg as conditioning in eight patients with RA. They observed that CY100 was associated with a short-lived response, but patients conditioned with CY200 had longer responses. Although there are some anecdotal reports of dramatic responses in patients with RA after ASCT, 32,33 the place of ASCT in the treatment of refractory RA is still an open question. At present, pilot studies are underway and, when issues of patient selection and optimal conditioning as well as other technical aspects are clearer, a formal randomized multicentre trial comparing ASCT with other treatment options (eg tumour necrosis factor alpha-antibody therapy) should be initiated. Haematological autoimmune diseases Only individual case reports are available on the treatment of refractory idiopathic thrombocytopenia (ITP) with ASCT. Lim et al. 40 described complete remission after ASCT in two patients with refractory ITP. On the other hand, some investigators 41,42 observed no significant effect of ASCT in their ITP patients. More experience is thus needed to find out whether ASCT can change the natural history of ITP and which patients, if any, may benefit from this approach. Other potential indications in this field include severe forms of autoimmune haemolytic anaemia (AIHA) and Evans syndrome (combination of ITP and AIHA).

3 Practical aspects of stem cell transplantation in autoimmune diseases Patient selection Patient selection is at present one of the major challenges in this field. Treatment of end-stage ADs with widespread irreversible tissue damage with ASCT may impose higher treatment-related risks with perhaps minimal clinical benefit. On the other hand, risks of this form of experimental therapy are hard to accept from an ethical point of view in patients with early or less severe diseases. The patient should have active AD which is resistant to current therapy or, alternatively, current therapies impose excessive toxicity. In addition, the patient should be capable of tolerating the risks of high-dose therapy. At the point of patient selection, primary physicians caring for these patients (eg rheumatologists, neurologists) are of paramount importance. They should discuss thoroughly with a particular patient all of the available treatment options. Thereafter, further discussions about practical aspects of ASCT may then be arranged with the personnel of the transplant team. In addition to written informed consent, acceptance by local ethical committee or institutional review board is desirable before proceeding to ASCT. Origin of progenitor cells To date, most ASCTs for ADs have been performed with the support of peripheral blood progenitor cells by analogy with current practices in patients with various malignant diseases. 43 Use of peripheral blood progenitor cells is associated with more rapid haematopoietic reconstitution and hence less toxicity compared to the use of marrow stem cells for haematopoietic rescue. 44 It is currently unknown whether different compositions of these grafts 45 have any impact on immune reconstitution 46 and the ultimate success of ASCT in the treatment of ADs. Analysis of the EBMT/EULAR database may give clues about the efficacy, toxicity and feasibility of various mobilisation protocols in patients with ADs. Finally, a randomised study may be necessary to further clarify this point. Graft processing Some human data suggest that patients transplanted with unmanipulated autologous progenitor cells experienced relapse or refractoriness of their AD. 26 Thus T celldepletion of the graft has been suggested. 4 Evaluating the efficacy of various graft processing methods for long-term success of ASCT in ADs requires prospective studies. Effective T cell depletion may cause prolonged severe immunosuppression and hence increase the risk of late opportunistic infections. Conditioning therapy The main aim of the conditioning in patients with various ADs is to ablate the immune system in order to achieve remission. Various types of T lymphocytes including memory cells are thought to be important in this respect. It is obvious that various conditioning protocols differ both with regard to their organ toxicity as well as to their T cell killing capacity. Whether the latter point turns out to be of clinical significance for long-term success of ASCT in the treatment of ADs is at present unknown. Antithymocyte globulin is rather effective for in vivo T cell depletion and may therefore have additional effects in conjunction with the conditioning. Several conditioning regimens have been proposed in the EMBT/EULAR guidelines. 4 At present, there are no data on the relative efficacy of these regimens in patients with various ADs. High-dose CY (200 mg/kg) is obviously less toxic than other proposed regimens and has been used even without progenitor cell support. 50 There may also be disease-specific issues for conditioning. 353 Mobilisation of peripheral blood progenitor cells Consensus guidelines proposed by EBMT/EULAR 4 suggest mobilisation with either granulocyte colony-stimulating factor (G-CSF) alone or in combination with high-dose CY. There has been some concern regarding possible flare of AD following the use of G-CSF at least in patients with RA. 47 High-dose CY is apparently a more toxic mobilisation regimen than G-CSF alone. On the other hand, highdose CY is a rather effective immunosuppressive treatment as such and may give some estimate on the responsiveness of the disease in a given patient to high-dose immunosuppression as well as some impression on the ability of a particular patient to tolerate high-dose therapy. Limited data are at present available on peripheral blood progenitor cell mobilisation in patients with various ADs. Early studies suggest that patients with RA may mobilise well with G-CSF (5 g/kg/day). 48 Snowden and co-workers 49 have compared G-CSF mobilisation with either 5 or 10 g/kg/day in patients with active RA and concluded that the higher G-CSF dose was more effective, although there were some flares. Acute toxicity of ASCT Current data from the EBMT/EULAR database suggest a transplant-related mortality (TRM) of 8% in patients with ADs. 27 This figure seems to be higher than TRM in cancer patients after PBSCT, but is obviously critically dependent on patient selection. Haematopoietic engraftment is expected to be quick if peripheral blood progenitors are used for haematopoietic rescue. However, a majority of patients will experience neutropenic fever complicated by septicemia and/or pneumonia in some patients. Depending on the intensity of the conditioning therapy mucositis will ensue in most patients. Late effects of ASCT Long-term risks are important considerations. Late opportunistic infections are possible because full immune reconstitution may take several months or even a year. Effective T cell depletion may delay immunological recovery even further and increase the risk of late infections. Infertility is an important issue especially in younger

4 354 patients. This risk is dependent on the type of the conditioning regimen used, and also on the age and sex of the patient. In women, early artificial menopause may ensue after ASCT. Secondary malignancies constitute an important longterm consideration. These include acute leukaemia and myelodysplastic syndromes in particular. Both are wellknown complications of ASCT for malignant disease, 51,52 although they may be more dependent on the previous chemotherapy than on the conditioning regimen as such. It is not known whether patients with ADs are more prone to develop secondary malignancies after ASCT than cancer patients. Possible outcomes after ASCT in patients with autoimmune disease Taking into consideration that abnormal stem cells may be responsible for altered immune functions 53 and hence several secondary changes attributable in the pathophysiology of various ADs, allogeneic SCT might offer the only curative form of treatment for severe ADs. However, due to its toxicity, allogeneic SCT is at present not considered evaluable in these indications by most transplant teams. In the autologous setting at least three possible outcomes of ADs after SCT exist. First, the disease may be refractory to the conditioning therapy by analogy with experience in various malignant diseases. In this case more intensive conditioning may be helpful but will obviously increase toxicity. Response to earlier immunosuppressive therapy given as well as progenitor cell mobilization with high-dose CY may give some hints on the responsiveness of the AD in a particular patient. Another possible outcome of ASCT is amelioration of the clinical course of AD. This may turn out to be of clinical benefit by improving the quality of life and also reducing the need for other therapies including corticosteroids and alkylating agents. The third and most optimistic outcome is complete remission of AD. Preliminary experience suggests that this can be achieved at least in some patients with ASCT. Whether permanent cure is possible is currently unknown, but remissions lasting for years may suggest it is. It is possible that some form of immunomodulatory therapy might be needed after ASCT including cyclosporine or interferon or a combination of them in order to prevent relapse or progression of AD after immune reconstitution. Future perspectives Application of ASCT in the treatment of severe ADs is only at the beginning. Because prospective comparative studies are missing, it is impossible to judge whether this form of intensive treatment may have some place in our treatment armamentarium against severe ADs in the 2000s. Early data suggest some clinical benefits, but longer followup and more experience are definitely needed. Analysis of registry data and early pilot studies should facilitate the planning of prospective trials. For this goal, knowledge on optimal treatment protocol (mobilisation, graft processing, conditioning) is of crucial importance as well as knowledge of diseases and patient groups most likely to show clinical benefit from this approach. The protocols may well be disease-specific and comparison with the best non-transplant approach available (eg high-dose CY, biological therapies) will be a major point. In addition to optimising protocols, objective criteria for treatment response as well as immunological reconstitution should be determined. All patients with ADs undergoing stem cell mobilisation should be registered in an international registry (EBMT/EULAR) without delay. The patients should be treated along EBMT/EULAR guidelines 4 and as many patients as possible treated within prospective protocols. Although most investigators consider allogeneic SCT at present too toxic for treatment of ADs, the situation may change soon. T cell depletion of allografts may decrease the incidence and mortality caused by GVHD. Non-myeloablative conditioning 54 may further decrease the toxicity of the procedure. These factors may reduce the TRM associated with allografting considerably and hence change the balance between risks and benefits. Other possibly useful strategies for future trials may include in addition to low-intensity conditioning, use of monoclonal antibodies (anti-cd4 or anti-cd8), T cell co-stimulatory blockage and eventually use of cyclosporine or mycophenolate mofetil for post-transplant immunomodulation. 55 Although some enthusiasm in this field exists, at present experience on ASCT in the treatment of human ADs is still in its infancy. Only through international co-operation and prospective well-planned studies, can the place of stem cell transplantation in the therapy of severe autoimmune diseases be further clarified. Note added in proof After the completion of this manuscript, Tyndall and coworkers published experience on ASCT in 74 patients with various ADs (Tyndall et al. Autologous haematopoietic stem cell transplants for autoimmune disease feasibility and transplant-related mortality. Bone Marrow Transplant 1999; 24: ). This analysis forms an important basis for future clinical trials in this field. References 1 Brooks PM, Atkinson K, Hamilton JA. Stem cell transplantation in autoimmune diseases. J Rheumatol 1995; 22: Marmont AM, van Bekkum DW. Stem cell transplantation for severe autoimmune diseases: new proposals but still unanswered questions. Bone Marrow Transplant 1995; 16: Marmont A. Tyndall A, Gratwohl A, Vischer T. Haemopoietic precursor-cell transplants for autoimmune diseases. Lancet 1995; 345: Tyndall A, Gratwohl A. 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